Adamantyl-s-triazines



United States Patent F ice 3,471,491

Patented Oct. 7, 1969 is fused with dicyandiamide or a substituted dicyanidi- ADAMANiYLZSITRIAZINES amide (substituted cyanoguanidine) and the substrtuted biguanide hydrochloride is recovered from the reaction V kt hl i fi i g E k gfi g z gfig i gf gzyf%a ik? mixture. Alternatlvely, the hydrochloride of the primary a corporation f Delaware 5 or secondary amine is reacted with sodium dicyanamide in No Drawing. Filed Aug. 28, 1967, Ser. No. 663,481 aqueous butanol to yield the adamantyl substuted Int. Cl. 'C07d 55/20 cyandiamide, which is then fused with the hydrochloride U.S. Cl. 260-2493 8 Claims of the appropriate primary or secondary amine.

Suitable starting amines for compounds of Formula 10 I include for example, l-adamantylamine, 3-methyl-1- ABSTRACT OF THE DISCLOSURE adamantyla-mine, 3-phenyl-l-adamantylamine, 3-fiuoro, 3-

This invention relates to new adamantyl-s-triazines Chlofo, 3-bI0II10 y which ar usef 1 a i i bi l d h l i methyl-l-adamantylamine as well as the adamantyl-lower agents. alkylamines and the N-alkyl compounds corresponding to the above.

Suitable dicyandiamides (cyanoguanidines) for the preparation of compounds of Formula I include dicyan- This invention relates to new adamantyl-s-triazines of the formula R l C H2 [CH2 H2 1 3 GH -CH R N R a-c m-(ca) --u---c n Ba 2 n g 4 c R H c (I) 2 and acid-addition salts thereof. diamide, 3-cyano-l-methylguanidine, 3-cyano-1-ethyl- In the above formula R and R each represents hydroguanidine, 3-cyano-l-propylguanidine, 3-cyano-1-isopropgen, halogen, lower alkyl, lower alkoxy, phenyl or phenylylguanidine, 3-cyano-l-isobutylguanidine, 3-cyano-l,1- lower alkyl (the R's can be the same or different), R diethylguanidine and 3-cyano-1-methyl-l-benzylguanidine represents hydrogen or lower alkyl, R represents hydroamong others. gen, lower alkyl or halo-lower alkyl, R and R each The bases of Formula I form acid-addition salts with a represents hydrogen, lower alkyl or phenyl-lower alkyl variety of inorganic and organic acids. Such salts include, and n represents 0, 1 or 2. for example, the hydrohalides, e.g., hydrochloride, hydro- The lower alkyl groups represented by the symbols R bromide, etc., sulfate, phosphate, nitrate, sulfonates, e.g., are straight or branched chain aliphatic hydrocarbon camphorsulfonate, benzenesulfonate, toluenesulfonate,

radicals such as methyl, ethyl, propyl, isopropyl, butyl, etc., citrate, oxalate, ascorbate, acetate, tartrate, salicylate, s-butyl, t-butyl, amyl, and the like. The lower alkoxy and 40 and the like. It is frequently most convenient to isolate phenyl-lower alkyl groups are radicals of the same charthe compound by forming the acid salt by reaction with acter including an oxygen atom or phenyl group, respecan inorganic or organic acid and precipitating it in a tively. The halo-lower alkyl groups include one or more medium in which it is insoluble. The free base may then halogens attached to an alkyl group of the character beobtained by neutralization.

described, e.g., chloromethyl, bromomethyl, dichloroeth- The new compounds of this invention are useful as yl, trifluoromethyl, and the like. antimicrobial agents, e.g., as antiviral agents, for example The new compounds of Formula I are produced from against influenza virus such as A-PR8 or hepatic virus compounds of the formula such as MHV or as antibacterial agents for example,

3 R II II (ca u---c --mt--c -N 2 n '1 n wherein the symbols have the same meaning as in against Staphylococci or Diplococci. They may be used Formula I, by reaction with a carboxylic acid or derivaas antiseptic or disinfectants for control or elimination tive thereof having the formula of airborne or environmental microbes, e.g., in sprays, R2 aqueous solutions, emulsions or suspensions of up to about 10% concentration. They may also be used orally R2 having the Same meaning as in Formula I and X or parenterally to combat microbial infestation of such representing the residual moiety of the acid, acid halide, organisms i ni l species affected by th m by oral or acid anhydride or ester. The reaction of the compound of parenteral d i i t ti f 5 t 40 mgjkg, three or Formula I with the acid or derivative is effected in alcofour times daily of a compound f F r l 1 or a physiholic med u With or Without a basic Catalyst Suitable ologically acceptable acid-addition salt thereof (or basic aq 01' d6f iVatiYe$ include example formic acid, salt when R is hydrogen) in conventional dosage forms tnchloroacetrc acid, acetic anhydride, acetyl chloride, and h as bl capsules, i j t bl s, th lik ethyl formate. The compounds of this invention also are hypoglycemic Qompolmds of Formula 11 y be producfid y a 7 agents which are effective in lowering blood sugar convar ety of methods, The hydrochloride of a pr1mary 0r tent in animal species. Long duration of action is a notesecondary amine, containing the des1red ada-mantyl group, worthy feature. They may be administered orally in the form of tablets, capsules or elixirs, or the like, by incorporating the appropriate dosage (e.g., about 10 to 50 mg./kg. three to four times daily) of the base of Formula I or a physiologically acceptable acid-addition salt in a conventional vehicle together with excipients, lubricants, preservatives, stabilizers, and the like, as required, according to accepted pharmaceutical practice.

The following examples are illustrative of the invention. All temperatures are expressed in the centigrade scale.

EXAMPLE 1 Preparation of 2-( l-adamantylamino)-4-amino-s-triazine (1) Preparation of 1-(1-adamantyl)biguanide hydrochloride.A finely ground mixture of 9.38 g. of adamantylamine hydrochloride and 4.2 g. 'of dicyandiamide is heated on an oil bath to 170 (external temperature of 200). The molten mass solidifies at this point and the mixture is maintained at 170 for one hour. After cooling, the hard solid cake is dissolved in 700 ml. of absolute alcohol and filtered. Addition of N-hexane results in the precipitation of 7.2 g. of a white solid, showing a @N absorption at 4.4 14. The above material is chromatographed over neutral alumina, and the fraction showing no nitrile absorption is concentrated and crystallized from alcohol-hexane to give 2.5 g. of l-(l-adamantyl)biguanide hydrochloride, M.P. 260-261 (2) Preparation of 2-(l-adamantylamino)-4-amino-striazine.To a cooled solution of 5.4 g. (0.02 mole) of 1-(l-adamantyl)biguanide hydrochloride in 200 ml. of methyl alcohol, 30 ml. of a 1.6% solution of sodium in dry methyl alcohol is added, followed by a solution of 1.5 g. of ethyl formate in 10 ml. of methanol. In fifteen minutes a precipitate appears, and the reaction mixture is stirred overnight at room temperature. The mixture is diluted with 50 ml. of water, cooled and filtered to give 4.2 g. of white solid. It is crystallized twice from isopropyl alcohol and dried at 120 in vacuo to give 3.2 g. of 2-(1- adamantylamino)-4-amino-s-triazine as shiny white plates,

EXAMPLE 2 Preparation of 2-[(l-adamantylmethyl)amino]-4-aminos-triazine P 5.16;]. (:0 of acid chloride) max (2) Preparation of 1 adamantanecarboxamide-1- adamantanecarboxylic acid chloride (35 g.) dissolved in 70 ml. of dry tetrahydrofuran, is added to a well-cooled aqueous ammonia solution. A white precipitate appears and the mixture is then stirred for 0.5 hour. The precipitate is filtered, washed with water to neutrality and dried over phosphorus pentoxide in vacuo to give 30.1 g. of l-adamantanecarboxamide; M.P. 186-1875";

A 5.95 (C=O of amide) max (3) Preparation of 1-adamantylmethylamine.-To a well-stirred suspension of 30 g. of lithium aluminum hydride in 1000 ml. of dry ether, 27 g. (0.15 mole) of l-adamantanecarboxamide is added in portions over a period of 1.5 hour. After the addition, the reaction mixture is stirred at room temperature for 1 hour, and then is refluxed with stirring for 4 hours, and finally is allowed to stand overnight at room temperature. The suspension is well-cooled and 50 ml. of water is added dropwise with vigorous stirring. This is followed by the addition of ml. of 10% sodium hydroxide solution. The ethereal layer is separated and the solid is extracted three times with ether. The combined ethereal layer is dried (MgSO and evaporated in vacuo to give 14.5 g. of product.

(4) Preparation of l-adamantylmethylamine hydrochloride.-l-adamantylmethylamine (14.5 g.) is dissolved in 50 ml. of anhydrous ether and 200 ml. of ethereal hydrogen chloride is added. The precipitated hydrochloride (18.1 g.) is collected and crystallized from methanol ether to give l-adamantylmethylamine hydrochloride as shiny white needles, M.P. over 280.

(5) Preparation of 2-[(1-adamantyl ethyl)amino]-4- amino-s-triamine-Following the procedure of Example 1 (steps 1 and 2) but substituting l-adamantylmethylamine hydrochloride, there is obtained 2-[(1-adamantylmethyl)amino]-4-amino-s-triazine, M.P. 2445-2465".

EXAMPLE 3 Preparation of 2-[(1-adamantylethyl)amino]- 4-amino-s-triazine (1) Preparation of l-adamantylacetic acid.-A solution of 25 g. of l-bromoadamantane in 100 g. of dichloroethylene is added dropwise during 1.5 hours to 100 ml. of sulphuric acid (90%) containing 18 g. of borontrifiuoride. The temperature is maintained between 810. After stirring for three hours at 10, crushed ice is gradually added, and the mixture diluted with water. The crude precipitate (26.5 g.) is dissolved in 10% sodium hydroxide solution, and the cloudy solution is extracted once with ether. The basic solution is cooled, and acidified with 5% hydrochloric acid. The l-adamantylacetic acid that precipitates is collected and dried to give 21.5 g. of white solid, M.P. -133, the analytical sample crystallizes from methanol-water as long white needles; M.P. 134-136.

Analysis.Calcd for C H O C, 74.19; H, 9.34. Found: C, 74.24; H, 9.84.

(2) Preparation of l-adamantaneacetic acid chloride is prepared similar to l-adamantanecarboxylic acid chloride but using l-adamantaneacetic acid (Example 1 (1)) as starting material.

(3) Preparation of l-adamantaneacetamide is prepared similar to l-adamantanecarboxamide (Example 1 (2)), M.P. 166-168.

(4) Preparation of l-adamantylethylamine hydrochloride-This compound is prepared similar to l-adamantylmethylamine hydrochloride (Example 2 (3) and (4)). It separates as white crystals from methanol-ether, M.P. over 280.

(5 Preparation of 2-[( 1-adamantylethyl)amino]-4- amino-s-triazine.Following the procedure of Example 1 (steps 1 and 2) but substituting l-adamantylethylamine hydrochloride, there is obtained 2-[(1-adamantylethyl) amino]-4-amino-s-triazine.

Similarly by reacting the indicated adamantyl biguanide, with the indicated carboxylic acid with derivative, in the procedure of Example 1 when n is 0, or in the procedure of Example 2 when n is 1, or in the procedure of Example 3 when n is 2, the corresponding substituted adamantyl-s-triazine is obtained.

Adam'antyl biguanide Carboxylic acid or its derivative R -COOC H 6 Adamantyl-s-triazine Example R=H, -R=H, R =H, R =H, R -R =R =OH n=1.

Example 16: R=CF R=H, R =H, R =H, R1 N R3:R4=C2H5, ":0. R0 OH l c/ The invention may be variously otherwise embodied i 2 K F within the scope of the appended claims.

N What is claimed is:

3 1. A compound of the formula H T fllzcl'ia R1 R3 CH -CH a-c H c (CH N-- c N c N ,N 4 B2 \c/ 1 32 Example 4: R=CH R=H, R =H, R =H, wherein R and R each is hydrogen, halogen, lower alkyl, R =R =H, n =0. lower alkoxy, or phenyl-lower alkyl, R is hydrogen or Example 5: R=CH R=H, R =H, R =H, lower alkyl, R is hydrogen, lower alkyl or halo-lower R =R =H, n=1. alkyl, R and R each is hydrogen, lower alkyl or phenyl Example 6: R=OCH R=H, R =H, R =H, lower alkyl, and n is 0, 1 0r 2, and salts thereof.

2. A compound according to claim 1 wherein R, R R R R and R are all hydrogen and n is 0.

3. A compound according to claim 1 wherein R, R R R R and R are all hydrogen and n is l.

4. A compound according to claim 1 wherein R, R R R R and R are all hydrogen and n is 2.

5. A compound according to claim 1 wherein R, R, R and R are all hydrogen, R and R each is lower alkyl and n is l.

6. A compound according to claim 1 wherein R, R", R and R are all hydrogen, R and R each is methyl and n is 1.

7. A compound according to claim 1, wherein R is methyl, R R R R and R are all hydrogen and n is 0.

.8. A compound according to claim 1, wherein R is trifluoromethyl, R R and R are all hydrogen, R and R each is ethyl and n is 0.

References Cited UNITED STATES PATENTS 2/ 1967 Schwarze et al. 260249.9 XR

1965, abstracted.

Chemical Abstracts, vol. 63, cols. 516-7 (1965).

HENRY R. JILES, Primary Examiner JOHN M. FORD, Assistant Examiner U.S. Cl. X.R. 

